title: MD-2 is involved in the stimulation of matrix metalloproteinase-1 expression by interferon-γ and high glucose in mononuclear cells - a potential role of MD-2 in Toll-like receptor 4-independent signalling.
abstract: We reported recently that treatment of diabetic apolipoprotein E-deficient mice with the Toll-like receptor 4 (TLR4) antagonist Rs-LPS, a lipopolysaccharide isolated from Rhodobacter sphaeroides, inhibited atherosclerosis. Since it is known that Rs-LPS antagonizes TLR4 by targeting TLR4 co-receptor MD-2, this finding indicates that MD-2 is a potential target for the treatment of atherosclerosis. In this study, we determined if MD-2 is involved in the gene expression regulated by signalling pathways independent of TLR4. Given that interferon-γ (IFNγ) and hyperglycaemia play key roles in atherosclerosis, we determined if MD-2 is involved in IFN-γ and high-glucose-regulated gene expression in mononuclear cells. Results showed that IFN-γ and high glucose synergistically stimulated matrix metalloproteinase 1 (MMP-1), a proteinase essential for vascular tissue remodelling and atherosclerosis, in U937 mononuclear cells, but Rs-LPS inhibited the MMP-1 stimulation. To provide more evidence for a role of MD-2 in IFN-γ-stimulated MMP-1, studies using antibodies and small interfering RNA demonstrated that MD-2 blockade or knockdown attenuated the effect of IFN-γ on MMP-1. Furthermore, studies using PCR arrays showed that MD-2 blockade had a similar effect as IFN-γ receptor blockade on the inhibition of IFN-γ-stimulated pro-inflammatory molecules. Although these findings indicate the involvement of MD-2 in IFN-γ signalling, we also observed that MD-2 was up-regulated by IFN-γ and high glucose. We found that MD-2 up-regulation by IFN-γ played an essential role in the synergistic effect of IFN-γ and LPS on MMP-1 expression. Taken together, these findings indicate that MD-2 is involved in IFN-γ signalling and IFN-γ-augmented MMP-1 up-regulation by LPS.
authors.affiliation: Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Lu
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Li
authors.forename: Devadoss J
authors.initials: DJ
authors.lastname: Samuvel
authors.forename: Junfei
authors.initials: J
authors.lastname: Jin
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.forename: Maria F
authors.initials: MF
authors.lastname: Lopes-Virella
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology*; D002239:Carbohydrate Metabolism, Inborn Errors / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000276:immunology; D005991:Glycerol Kinase / Q000172:deficiency* / Q000276:immunology; D006801:Humans; D000075262:Hypoadrenocorticism, Familial; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D012242:Rhodobacter sphaeroides / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D019138:Antibodies, Blocking; D001057:Apolipoproteins E; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D005991:Glycerol Kinase; D020781:Matrix Metalloproteinase 1; D005947:Glucose
keywords: MD-2; Toll-like receptor; inflammation; interferon-γ; mononuclear cells